Activation of meiosis-specific genes is associated with depolyploidization of human tumor cells following radiation-induced mitotic catastrophe.
Activation of meiosis-specific genes is associated with depolyploidization of human tumor cells following radiation-induced mitotic catastrophe.
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DOI：
10.1158/0008-5472.can-08-3364
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Mackey MA
中科院分区：
文献类型：
--
作者：
Ianzini F;Kosmacek EA;Nelson ES;Napoli E;Erenpreisa J;Kalejs M;Mackey MA
癌症的组织学特征通常是出现非整倍体或多倍体的大细胞。非整倍性和多倍性是辐射诱导的有丝分裂灾难（MC）的标志，这是暴露于各种细胞毒性和遗传毒性试剂的p53功能受损的肿瘤细胞中发生的常见现象。MC的特征在于有丝分裂调节因子的表达改变、不适时和异常的细胞分裂、延迟的DNA损伤和形态学改变。我们在这里报告说，经历辐射诱导的MC的细胞是更具可塑性的倍性，这种可塑性使他们能够重组其遗传物质，通过减少分裂，产生较小的细胞形态与控制细胞无法区分。与大规模数字细胞分析系统（LSDCAS）进行的实验进行了讨论，表明通过辐射诱导的MC形成的多倍体癌细胞的一小部分可以存活，并开始一个过程中的去多倍体，产生各种结果。虽然大多数多极分裂失败并发生细胞融合，但其中一些分裂是成功的，并产生了以不同倍性为特征的各种细胞后代。在这些倍性表型中，经常看到与未处理的对照细胞难以区分的小单核细胞的后代。我们在这里报告的证据表明，减数分裂特异性基因表达的多倍体细胞在去多倍化。肿瘤细胞可能利用从促有丝分裂到促减数分裂分裂方案的暂时变化来促进去多倍化并恢复肿瘤细胞群的增殖状态。这些事件可能是体内发生肿瘤进展和治疗耐药性的机制。
Cancer is frequently characterized histologically by the appearance of large cells that are either aneuploid or polyploid. Aneuploidy and polyploidy are hallmarks of radiation-induced mitotic catastrophe (MC), a common phenomenon occurring in tumor cells with impaired p53 function exposed to various cytotoxic and genotoxic agents. MC is characterized by altered expression of mitotic regulators, untimely and abnormal cell division, delayed DNA damage, and changes in morphology. We report here that cells undergoing radiation-induced MC are more plastic with regards to ploidy and that this plasticity allows them to reorganize their genetic material through reduction divisions to produce smaller cells morphologically indistinguishable from control cells. Experiments conducted with the Large Scale Digital Cell Analysis System (LSDCAS) are discussed that show that a small fraction of polyploid cancer cells formed via radiation-induced MC can survive and start a process of depolyploidization that yields various outcomes. While most multipolar divisions failed and cell fusion occurred; some of these divisions were successful and originated a variety of cell progeny characterized by different ploidy. Among these ploidy phenotypes, a progeny of small mononucleated cells, indistinguishable from the untreated control cells, is often seen. We report here evidence that meiosis-specific genes are expressed in the polyploid cells during depolyploidization. Tumor cells might take advantage of the temporary change from a pro-mitotic to a pro-meiotic division regimen to facilitate depolyploidization and restore the proliferative state of the tumor cell population. These events might be mechanisms by which tumor progression and resistance to treatment occur in vivo.